The present invention relates to methods and formulations for increasing intestinal function, which may be used for treating short bowel syndrome.
Short bowel syndrome (SBS) is defined as an intestinal failure following the loss of intestinal length or competence below the minimal amount necessary for the absorption of nutrients and a normal nutritional status [Sigalet D L. Short bowel syndrome in infants and children: an overview. Semin Pediatr Surg 2001; 10:49-55; Vanderhoof J A. Short bowel syndrome. Neonat Gastroenterol 1996; 23:377-86; Booth I W, Lander A D. Short bowel syndrome. Bailliere's Clin Gastroenterol 1998; 12:739-72].
SBS typically follows resection of 50% or more of the small intestine and is associated with diarrhea, steatorrhea, dehydration, electrolyte disturbances, malabsorption and progressive malnutrition [Vanderhoof J A. Short bowel syndrome. Neonat Gastroenterol 1996; 23:377-86; Booth I W, Lander A D. Short bowel syndrome. Bailliere's Clin Gastroenterol 1998; 12:739-72]. SBS is a common problem in pediatric surgery and occurs in newborns and infants suffering from necrotizing enterocolitis (NEC), intestinal atresia and volvulus requiring massive intestinal resection. In adults, Crohn's disease, radiation enteritis and massive resections due to catastrophic mesenteric vascular events, intestinal obstruction, and trauma represent the more common causes of SBS [DiBaise J K, Young R J, Vanderhoof J A. Intestinal rehabilitation and the short bowel syndrome. Am J Gastroenterol 2004; 99:1386-95]. SBS remains a significant cause of infant morbidity and mortality despite the availability of total parenteral nutrition (TPN), advances in resuscitation, availability of potent antibiotics, and modern techniques of organ support [Coran A G, Spivak D, Teitelbaum D H. An analysis of the morbidity and mortality of short bowel syndrome in the pediatric age group. Eur J Pediatr Surg 1999; 9:228-30].
The key to survival after massive small bowel resection is the ability of the residual intestine to adapt. In this setting, adaptation means progressive recovery from intestinal failure throughout which the small bowel increases its absorptive surface area and its functional capacity in an attempt to meet the body's metabolic and growth needs [O'Brien D P, Nelson L A, Huang F S, Warner B W. Intestinal adaptation: structure, function, and regulation. Semin Pediatr Surg 2001; 10:56-64]. Intestinal adaptation constitutes the best option for patients with SBS. In humans, intestinal adaptation begins within 24-48 hours of resection and includes morphologic (structural adaptation) and functional changes (functional adaptation) of the residual bowel. Structural adaptation includes increasing bowel diameter and length, villi elongation, deepening of the crypts, and increasing the rate of enterocyte proliferation, finally resulting in increased absorptive surface area and in increased numbers of enterocytes. Functional adaptation entails modifications of the brush border membrane permeability and up-regulation of carrier-mediated transport, ultimately resulting in increased nutrient absorption by isolated enterocytes. Although intestinal transplantation (IT) has emerged as a feasible alternative in the treatment of children with SBS during the last two decades, intestinal adaptation remains the only chance for survival in a subset of these patients. Considerable research over many years has focused on the identification of those trophic factors that may promote bowel absorption after massive intestinal resection and provide a successful outcome in patients with SBS. These factors include nutrients and other luminal constituents, gastrointestinal secretions, hormones and peptide growth factors [O'Brien D P, Nelson L A, Huang F S, Warner B W. Intestinal adaptation: structure, function, and regulation. Semin Pediatr Surg 2001; 10:56-64].
Another area in which there has been a considerable research effort over the last four decades is intestinal ischemia-reperfusion. Restoration of blood flow following intestinal ischemia is necessary to maintain cell function and viability; however, the reintroduction of oxygen can initiate a cascade of events that exacerbates intestinal tissue injury. The mechanisms of intestinal injury following ischemia-reperfusion event include nonspecific damage induced by ischemia per se and damage caused by reperfusion. Intestinal ischemia induces intestinal mucosal cell death, which is attributed mainly to a reduction of oxygen supply relative to metabolic demands, depletion of cellular energy stores and accumulation of toxic metabolites. The reperfusion phase may significantly exacerbate ischemia-induced mucosal injury via the formation of reactive oxygen species and reactive nitrogen species [Carden, D. L., Granger, D. N. J. Pathol., 2000, 190: 255; Granger, D. N., et al., Acta. Physiol. Scand. Suppl. 548: 47, 1986] and changes in lipid mediator synthesis [Tadros et al., Ann. Surg. 231: 566, 2000; Mangino et al., Cryobiology. 33: 404, 1996]. Additionally, an infiltration of intestinal wall by polymorphonuclear leucocytes and mast cells, which release the cytokines, growth factors, or other molecules leads to increased bowel permeability, gut barrier dysfunction, translocation of bacteria and bacterial products into the systemic circulation, causing multiple organ failure and death [Schoenberg et al., 1991, Gut, 32: 905; Yamamoto et al., 2001, J. Surj Research, 99:134].
Although necrosis is responsible for the intestinal cell death during the ischemic phase, apoptosis has recently been recognized to be a key phenomenon in enterocyte turnover and gut barrier function following IR insult [Noda et al., Am J Physiol, 1998, 274: G270]. Thus, reduction of apoptosis and stimulation of cell proliferation and differentiation following IR injury is a potential target for therapeutic intervention.
A number of nutrient substances have been evaluated in an attempt to maximize the adaptive response following IR injury and following resection of the small intestine. Diets high in glutamine, and high carbohydrate-low fat diets have been studied [Byrne, T. P., et al., 1995, Annals of Surgery 222(3):254-5; Scolapio, J. S. et al., 1997 Gastroenterology 113(4):1402-5; Sax, H., 1998, Journal of Parenteral and Enteral Nutrition 26(2):123-8].
Formulas containing amino acids have been studied in an attempt to avoid intact protein irritability and digestion [Bines, J. F. et al., 1998, Journal of Pediatric Gastroenterology & Nutrition 26(2):123-8]. Dietary restrictions of insoluble fiber, oxalates, and lactose have also been proposed [Lykins, T. S. et al., 1998, Journal of the American Dietetic Association 98(3):309-15] despite evidence that small amounts of lactose are tolerated [Marteau, P. M. et al., 1997, Nutrition 13(1):13-16]. Compositions comprising arachidonic acid and docosahexanoic acid have been proposed for improving the proliferative response during adaptation of the gastrointestinal tract for use in short bowel syndrome [U.S. Pat. Appl. 0010047036].
Hormones, such as growth hormone [Weiming et al., 2004, JPEN J Parenter Rectal-enteral Nutr. November-December; 28(6):377-81] and hormone related peptides (e.g., Glucagon-like peptide 2 and analogs thereof, U.S. Patent Application 0030162703) were shown to have a trophic effect on the intestine.
There is also a growing body of evidence suggesting that peptide growth factors may stimulate post-resection adaptive hyperplasia or improve intestinal recovery following intestinal ischemia. Peptide growth factors are divided into several families, including epidermal growth factor family, the transforming growth factor β family, the insulin-like growth factor (IGF) family, and the fibroblast growth factor family. In addition, a smaller number of peptide growth factors without structural similarities of the described families have also been identified and include hepatocyte growth factor and platelet-derived growth factor.
The insulin-like growth factor family includes three peptides: insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor II (IGF-II). Several experimental studies have suggested that both IGF-I and IGF-II are involved in to modulation of growth and differentiation of normal small bowel [Laburthe M. et al., 1988, Am J Physiol; 254: G457-G462] and following massive small bowel resection [Ziegler T R, Mantell M P, Chow J C et al. (1996) Gut adaptation and the insulin-like growth factor system: regulation by glutamine and IGF-1 administration. Am J Physiol 271: G866-875].
Lemmey and co-workers have demonstrated a positive effect of IGF-1 on body weight gain and intestinal absorptive function [Lemmey A B., et al., 1991, Am J. Physiol. February, 260(2 Pt 1):E213-9; Lemmey A B., et al., 1994, Growth Factors, 10(4):243-521 following bowel resection in a rat model. IGF-1 was shown to stimulate cell proliferation, increase villus height and promote nutrient absorptive capacity in an animal model of SBS [Olanrewaju H et al., 1992, Am J Physiol, 263: E282-286]. Ileal IGF-I mRNA expression in rats rose nearly twofold during intestinal adaptation after bowel resection, which was augmented with IGF-I administration [Ziegler et al., 1996, Am J Physiol, 271: G866-G875]. EGF and IGF-1 were shown to increase substrate absorption after small bowel resection in rats, and this increase in absorption persists after cessation of administration of these growth factors [Lukish et al., 1996, Gastroenterology, 110(Suppl): A818].
However, animal experiments and clinical trials using the above agents are at present inconclusive and there remains a widely recognized need for an intestinal tissue growth promoting agent which may be administered orally for the therapeutic treatment of various intestinal disorders, intestinal ischemic damage, impaired growth or loss of intestinal length.
The current advocacy of insulin therapy regimens involves subcutaneous injections and intravenous administration, since like other polypeptides, insulin is destroyed in the acidic environment of the stomach and by digestive enzymes of the pancreas and small intestine. Furthermore, insulin treatment is typically aimed at increasing the level of insulin in the blood (such as for insulin dependent diabetes), where the epithelial surface of the intestine itself presents an effective barrier to the absorption of insulin [Sukhotnik et al., 2002, J Surg Res. December; 108(2):235-42].
Accumulative evidence suggests a role of insulin in the growth and development of the small intestine. For example, insulin receptors are present on the luminal and basolateral membranes of enterocytes [Buts J P, De Keyser N, Marandi S, Maernoudt A S, Sokal E M, Rahier J, Hermans D. Expression of insulin receptors and of 60-kDa receptor substrate in rat mature and immature enterocytes. Am J Physiol Gastrointest Liver Physiol 273:G217-226, 1997)]. Additionally, insulin is present in human and pig colostrum and mature milk, substantiating its aforementioned potential role in small intestine growth and development.
Oral insulin was shown to possess a trophic effect on intestinal mucosa by stimulating ileal mass, mRNA and disaccharidase activity in the newborn miniature pig [Shulman et al., Pediatr Res. 1990 August; 28(2):171-512; Shulman R J, Tivey D R, Sunitha I, Dudley M A, Henning S J 1992. Effect of oral insulin on lactase activity, mRNA, and posttranscriptional processing in the newborn pig. J Pediatr Gastroenterol Nutr 14:166-172)]. In a recent clinical trial, the author has shown that enteral administration of insulin to preterm infants (26-29 weeks of gestational age) leads to a higher lactase activity and less feeding intolerance [Shulman R J, et al., Arch. Dis. Child. Fetal Neonatal Ed (2002); 88:F131-3].
Insulin was also shown to stimulate epithelial cell proliferation and differentiation of intestinal epithelial cells in vitro [Raj N. K. Sharma C. P., 2003, J Biomater Appl January 17(3):183-96]. Insulin accelerates enterocyte proliferation in the intestinal mucosa of suckling mice [Malone et al., Diabetes Res Clin Pract 2003 December; 62(3):187-95] and increases enzymatic activity of the dissacharidases [Buts J P, Duranton B, De Keyser N, Sokal E M, Maernhout A S, Raul F, Marandi S. Premature stimulation of rat sucrase-isomaltase (SI) by exogenous insulin and the analog B-Asp10 is regulated by a receptor-mediated signal triggering SI gene transcription. Pediatr Res 1998; 43:585-91]. Furthermore, insulin-receptor densities are selectively associated with intestinal mucosa growth in neonatal calves [Kojima H. 1998, Assoc Am Physicians, May-June; 110(3):197-206].
Moreover, Buts et al. had demonstrated preferential localization of insulin binding sites to the intestinal crypt cells, regardless of the age of the animal [Buts J P, De Keyser N, Marandi S, Maernoudt A S, Sokal E M, Rahier J, et al. Expression of insulin receptors and of 60-kDa receptor substrate in rat mature and immature enterocytes. Am J Physiol Gastrointest Liver Physiol (1997); 273:G217-261
Thus, prior art studies suggest that insulin is highly active in promoting lactase activity, mRNA levels and ileal mass when administered to healthy preterm infants or animal models, but does not suggest oral or enteral administration of insulin for increasing intestinal function in non-healthy infants.
The present inventors have previously shown that physiological concentrations (i.e., about 100 μu in maternal milk and 700 μu in colostrum) of insulin formulated in infant formula can be used for the manufacture of formulas which are similar to human milk. Such formulas are expected to protect new born babies from the development of Type-1 diabetes and to improve development and maturation of infants intestine (U.S. Pat. No. 6,399,090).
To date oral administration of insulin (not included in infant formulas) has not been suggested for improving intestinal function humans weaned of infant formula or non-human animal subjects.